Abstract
Epstein–Barr virus-positive diffuse large B-cell lymphoma (EBV+DLBCL) is an aggressive malignancy that is largely resistant to current therapeutic regimens, and is an attractive target for immune-based therapies. Anti-programmed death-1 (PD-1) antibodies showed encouraging anti-tumor effects in both preclinical models and advanced solid and hematological malignancies, but its efficacy against EBV+DLBCL is unknown. Herein, we performed experiments using co-culture system with T cells and lymphoma cell lines including EBV+DLBCL and EBV-DLBCL [including germinal center B-cell like (GCB)-DLBCL and non-GCB-DLBCL] in vitro. We show that lymphoma cells augmented the expression of PD-1 on T cells, decreased the proliferation of T cells, and altered the secretion of multiple cytokines. However, through PD-1 blockade, these functions could be largely restored. Notbaly, the effect of PD-1 blockade on antitumor immunity was more effective in EBV+DLBCL than that in EBV-DLBCL in vitro. These results suggest that T-cell exhaustion and immune escape in microenvironment is one of the mechanisms underlying DLBCL; and PD-1 blockade could present as a efficacious immunotherapeutic treatment for EBV+DLBCL.
Highlights
The immune system plays an important role in the development of cancer [1,2] including hematologic malignancies [3]
Epstein–Barr virus-associated diffuse large B-cell lymphoma (EBV+DLBCL) is an aggressive malignancy that is largely resistant to current therapeutic regimens and is an attractive target for immune-based therapies [4]
We find that the effects of programmed death-1 (PD-1) blockade on antitumor immunity are more effective in EBV+DLBCL than that in EBV-DLBCL, PD-1 blockade could restore immune escape resulting in more efficient T-cell exhaustion in EBV+DLBCL
Summary
The immune system plays an important role in the development of cancer [1,2] including hematologic malignancies [3]. Epstein–Barr virus-associated diffuse large B-cell lymphoma (EBV+DLBCL) is an aggressive malignancy that is largely resistant to current therapeutic regimens and is an attractive target for immune-based therapies [4]. The efficacy of immune-targeted therapies in virus-related lymphomas has not been rigorously tested. The applicability of programmed death-1 (PD-1) blockade in the treatment of EBV +DLBCL has not been investigated so far. PD-1 is a member of the B7 receptor family, which plays an important role in the regulation of immune response [5]. The PD-1 receptor, in conjunction with ligands PD-LI and PD-L2, regulates the immune response primarily by downregulating the signals of the T-cell receptor
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